Aggregation of Therapeutic Antibodies: A Multiscale Molecular Dynamics Approach

Abstract

The aggregation of proteins is a major challenge in the development of novel antibody based therapeutics. Therapeutic antibodies are produced and stored in extremely high concentrations and generated under varying and unfavourable conditions for the stability of monomeric proteins. The aggregation of these proteins in solution can lead to serious consequences for patients in the form of the initiation of immune reactions, which have the potential to be fatal, and in the loss of clinical potency. Further to this, the type of aggregates formed by antibodies, and the processes that lead to their propagation, are relatively poorly understood. Thus by investigating these molecules as a model system we may find out more about other, more complex systems known to involve aggregation - including amyloids.Here we apply multiscale molecular dynamics simulations to investigate the aggregation of antibody fragments. using coarse-grained molecular dynamics (CG-MD) we are able to access much longer timescales than traditional atomistic methodologies, and to look at much larger ensembles of proteins. Converting back to atomistic detail then allows us to get a more detailed view of the interfaces between 2 proteins.CG simulations of systems containing 2 protein fragments give us insights into the specific interactions and, which surfaces on the molecular structures are involved in them. Simulations of much larger ensembles of proteins (from 4 and up to 16 antibody fragments) allow us to look the formation of larger aggregates, and can validate the surfaces discovered from simulations using only 2 fragments. Combining all these molecular dynamics methodologies we are able to gain insights into the most likely interactions between proteins, and on the most likely method of aggregation, and the potential structures of protein aggregates.